Our research program centers upon "The Synthesis and Application of Aromatic Materials" for the construction of complex natural products. Ours is one of only a handful of programs that aims to expand synthetic methods that pertain to aromatic compounds, and it fulfills a critical need by reducing the bottleneck found in the preparation of medicinally relevant compounds from aromatic motifs. Aromatic chemistry, once a thriving area of research and the basis of the dye industry, has largely been ignored because of its perceived maturity and simplicity. This proposal demonstrates that novel chiral electrophiles derived from aromatic systems can still make many important contributions to the synthesis of complex natural products and newly discovered medically relevant compounds. Natural products remain an important area of therapeutic research because they have been prescreened and employed by living systems for billions of years. They are often better tolerated in humans than entirely new compositions of matter. As such, natural products continue to provide a rich source of lead compounds for the treatment of a variety of diseases. Most medicinal agents used in chemotherapy today are derived from a natural product and most among these contain an aromatic motif. Over the past period, the PI has developed and choreographed a cascade for the low temperature preparation of o-quinone methides (o-QMs). The PI has successfully utilized this procedure for the preparation of exotic resorcinols, which have been further transformed by enantioselective oxidative dearomatization (EOD) into the versatile non-racemic synthons for construction of densely functionalized cyclohexadienone derivatives. The PI has demonstrated these new technologies in the total syntheses of mitorubrinic acid, epoxysorbicillinol, rishirilide B, the cleroindicins, diinsininone, scyphostatin derivatives, and several other natural products. These pursuits have also led to the development of other methods including novel procedures for o-quinone formation, enone epoxidation, and phenol dearomatization. For the coming grant period, the PI proposes to complete the synthesis of several challenging complex natural products known to be useful in the treatment of various diseases. These synthetic problems are relevant and challenging in all aspects including structural, functional and stereochemical complexity. The target compounds include the MRSA antibiotic oxysporidinone, the newly discovered nanomolar anti cancer agent illudin J1, the anti-oxidant tetrapetalone A, the antimitotic paecilospirone, and the nanomolar anti cancer agent berkelic acid. The proposed plans aim to lead to efficient preparations of these target compounds and to provide significant quantities of these materials for further biological testing. The strategies rely on inexpensive and pervasive aromatic compounds as building blocks. The probability for success is high and the work will undoubtedly lead to other fundamental improvements to chemical sciences as well as provide advancements for other areas of science relevant to drug discovery and design. PUBLIC HEALTH RELEVANCE: Organic synthesis is an enabling science that allows its practitioners to impact many areas of science including materials, biology, and medicine, often times unintentionally. This proposed research aims to develop and deploy several new synthetic methodologies for the construction of aromatic compounds. The methods will be used for the construction of five biologically active compounds for which supplies are limited and thereby ensure further medical testing for these compounds, which are of strong therapeutic interest. Persons with all levels of skill (undergrad through postdoc) will contribute to the specific aims of this proposal and benefit from this learning environment. They will undoubtedly continue onto jobs in the pharmaceutical industry. The skills and technology acquired will enable many areas of science.